Field of Invention
The present invention relates to a fluorinated 2-arylbenzo heterocyclic compound with high affinity to Aβ plaques and containing a chiral side chain substituent, and a preparation method and usage thereof.
Description of Related Arts
Alzheimer's disease (AD) is a progressive fatal neurodegenerative disease with the clinical manifestations including cognitive and memory impairment, and the impairment of the ability for performing activities of daily living, and accompanied with a variety of neuropsychiatric symptoms and behavioral disorders. AD has become a major disease ranking next to cancer, heart disease and stroke and being a serious threat to the health of the elderly. Statistics show that the average incidence rate of AD in people over 65 years is 6.6% and increases with age: 11% in people of 75-80 years old and 22% in people of over 80 years old. At present, China has a rapidly growing aging population. It is estimated that by 2050, the ratio of the elderly of over 60 years old or above will be more than 30%. Therefore, prevention of AD will be an arduous task, and study of early diagnosis of AD is extremely important.
The senile plaques (SPs) deposited outside the nerve cells in the brain and the neuro fibrillary tangles (NFTs) deposited inside the nerve cells in the brain are the two major pathological features of AD. However, its exact pathogenesis is unclear (Hardy J et al., Science, 2002, 297: 353-356). Studies have shown that the deposition of the Aβ plaques in the brain has already been occurring for 10-20 years before AD occurs (Braak, H et al., Acta Neuropathol, 1991, 82: 239-259). Currently, it is difficult to accurately diagnose clinical AD, which is diagnosed mainly by the evaluation of the patient's cognitive dysfunction. AD can be accurately diagnosed only with the SPs and NFTs found in the brain of a patient in an autopsy. Thus, although the causes of AD are unclear yet, early AD can still be diagnosed by an effective non-invasive molecular method in which the Aβ plaques in the brain are used as targets and a molecular probe with high affinity and selectivity to these targets is developed to implement a positron emission tomography (PET) scan (Cai L S et al. Curr Med Chem, 2007, 14: 19-52).
In the past 10 years, there have been a number of positron Aβ molecular probes put into clinical trials, such as the C-11-labeled PIB is the most widely used Aβ imaging agent currently, with which AD can be clearly identified in a patient from normal people. (Klunk W E et al., Annals of Neurology, 2004, 55: 306-319). However, the short half-life (20.4 min) of the C-11 nuclides has limited its application in clinical practice. Therefore, using the F-18-labeled nuclides with a long half-life as an Aβ imaging agent is the current trend of development. For instance, the PIB analogues[18F] GE-067 (Koole M et al., Journal of Nuclear Medicine, 2009, 50:818-22) and the stilbene derivates [18F] AV-45 (Wong D F et al., Journal of Nuclear Medicine, 2010, 51: 913-20) have been approved by FDA, and the commercial development of these compounds has been started.